Selamectin, has a chemical name of (5Z,25S)-25-cyclohexyl-4′-O-de(2,6-dideoxy-3-O-methyl-α-L-arabino-hexopyranosyl)-5-demethoxy-25-de(1-methylpropyl)-22,23-dihydro-5-(hydroxyimino)avermectin A1a (herein “a” indicates natural avermectin, in which the 25-substituent is (s)-sec-butyl, “A” indicates avermectin wherein the 5-substituent is methoxy, number “1” indicates avermectin wherein the double bond is at 22-23 position), and has a chemical formula of

Selamectin is produced by fermentation of new gene-recombined strain of Streptomyces avermitilis, and is a new compound belonging to avermectins. Such new generation antiparasitic drug is developed by Pfizer Inc., America, and is produced by structural modification of doramectin via chemical synthesis.
Selamectin has antiparasitic activity on both endoparasite (threadworm) and ectoparasite (arthropod insects). Having the same effect as other avermectins, selamectin causes rapid, lethal, and non-paralytic neuromuscular paralysis of insects by interfering the glutamic acid-controlling chloride ion channel of the insect. After being applied onto the skin of a cat or a dog, the drug is absorbed into blood, and a part of the drug enters into digestive tract and blood by oral when the animal grooms its hair. The pharmacokinetics results show that selamectin exhibits permanent absorption in blood plasma after topical external application. The experimental data show that selamectin accumulates on skin (in particular sebaceous gland), ensuring a permanent concentration of drug that is sufficient to kill parasitic on the hair. The skin scrapings collected 30 days after the application of the drug can still kill eggs and larva of flea. Therefore, in comparison to conventional similar drugs, selamectin can overcome the disadvantages of poor efficiency, easy recurrence, inconvenient, and poor resistance of pets, and can kill endoparasite and ectoparasite such as flea, heartworm, tick, Itch mite, and ear mite that afflict pet and their owners rapidly, efficiently, conveniently, and completely, and has high safety. Good effect can be obtained by either oral administration or injection.
The synthesis processes of selamectin are reported in the following references: U.S. Pat. No. 5,981,500, EP677054, WO94015944, and CN94101917, wherein selamectin is prepared from doramectin by hydrogenation, desugaring, oxidation and oximation. In the first step of hydrogenation, the compound of formula (II) is prepared by using Wilkinson's catalyst, and toluene as the solvent. The second step, desugaring, is carried out in isopropanol, using sulfuric acid. The third step, oxidation, is carried out in anhydrous ethyl ether, in the presence of active manganese dioxide. The fourth step, oximation, is carried out in anhydrous pyridine, using hydroxylamine hydrochloride. Finally, selamectin is obtained via purification by using silica gel column chromatography. Such process is the basic patented process for the preparation of selamectin, which has the disadvantages of long reaction route, low overall yield, and inconvenient industrial operation.
U.S. Pat. No. 6,906,184, EP1003764, WO99007721, CN98808106, etc. prepare selamectin via three-step chemical synthesis, using doramectin as the starting material. Firstly, the double bond at the C-22, 23 position is converted into single bond by addition reaction, via hydrogenation. The second step is oxidation, only the hydroxyl group at C-5 position is oxidized to ketone. The third step is oximation and desugaring, i.e. the ketone at C-5 position is oximated, while a sugar molecule is desugared, to obtain selamectin. Such process is the improved process of the basic patented process, developed by Pfizer Inc., wherein the reaction that obtains 5-oxime from the intermediate of oxidation product and hydroxylamine hydrochloride, and the hydrolysis step generating monosaccharide derivatives are carried out simultaneously, as a single concurrent reaction, which simplify the operation process significantly, and can reduce the processing and separation process, and thus improve the overall yield and quality of selamectin. However, active manganese dioxide is employed as the oxidant in the second step, with significant amount, which is difficult for after-treatment, and thus the industrial production will bring significant environmental problems. Isopropanol/water system is employed in the third step, i.e. oximation and desugaring, it has long reaction time and is unsuitable for improving the efficiency of industrial production.
Research On the Synthesis Process of Selamectin and Ethyl (R)-4-cyano-3-hydroxybutyrate (Shixiang Lv, Master's Thesis of Northeast Agricultural University, 2009) also uses doramectin as the starting material, wherein selamectin is synthesized via a three-step synthesis. The first step involves the preparation of the compound of formula (II) via catalytic hydrogenation, wherein the reaction condition is optimized, to obtain a yield of 95.8%. In the second step, i.e. oxidation, the intermediate II is prepared by oxidant A addition and oxidant A priming, respectively, and the yield is 93.4%. In the third step, i.e. oximation and desugaring, crude selamectin is obtained, and the optimized reaction conditions, i.e. triethylamine and 45° C., are determined by using triethylamine method and disodium hydrogen phosphate method, changing the reaction concentration, and carrying out reaction at room temperature, and then a yield of 75.5% is obtained. Finally, it is crystallized twice with solvent A, to obtain selamectin (purity >98.5%), and the overall yield is 55%. Such process is a successful improvement developed on the basis of the above mentioned two processes, and has the advantages of short reaction route and mild reaction conditions, and the overall yield is 55%. However, in the second step, i.e. oxidation, the oxidant after-treatment may generate a large amount of heavy metal wastewater, which may restrict the industrial production.
The present invention makes inventive development on the basis of the prior arts, overcomes the disadvantages of the above mentioned processes, and provides a novel synthesis scheme for selamectin, with easy-handled oxidant, short process period, high efficiency, and reduced pollution.